Synthesis of Biocompatible and Biodegradable Polyamidoamines Microgels via a Simple and Reliable Statistical Approach

Polyamidoamines (PAAs) are biocompatible and biodegradable polymers with a huge potential as biomaterials for pharmaceutical applications. They are obtained by the step-wise aza-Michael polyaddition of bifunctional or multifunctional amines with bisacrylamides in water. To the best of our knowledge, no synthetic protocols leading to hyperbranched PAAs as well as PAA microgels have been published so far. To fill this gap, a statistical approach was established in this work to fine-tune the aza-Michael polyaddition stoichiometry when a multifunctional co-monomer (b_f) is added to a mixture of bifunctional monomers with complementary functions (a₂ + b₂), possibly even in presence of a monofunctional co-monomer (b₁), for obtaining either microgels or hyperbranched polymers by a one-pot reaction. For this purpose, two new equations, obtained by reworking the classic Flory-Stockmayer equations, were successfully applied to the synthesis of different model systems, obtaining biocompatible microgels with tunable size distribution (200-500 nm) and properly designed end-chains in a simple and straightforward way. The same mathematical approach allowed us to empirically evaluate the actual number of active reactive functions of the co-monomers. A number of selected systems, being evaluated for their cytotoxicity in vitro, proved highly cytocompatible and, therefore, endowed with great potential for pharmaceutical and medical applications.